title: Two Distinct Categories of Focal Deletions in Cancer Genomes.
abstract: One of the key questions about genomic alterations in cancer is whether they are functional in the sense of contributing to the selective advantage of tumor cells. The frequency with which an alteration occurs might reflect its ability to increase cancer cell growth, or alternatively, enhanced instability of a locus may increase the frequency with which it is found to be aberrant in tumors, regardless of oncogenic impact. Here we've addressed this on a genome-wide scale for cancer-associated focal deletions, which are known to pinpoint both tumor suppressor genes (tumor suppressors) and unstable loci. Based on DNA copy number analysis of over one-thousand human cancers representing ten different tumor types, we observed five loci with focal deletion frequencies above 5%, including the A2BP1 gene at 16p13.3 and the MACROD2 gene at 20p12.1. However, neither RNA expression nor functional studies support a tumor suppressor role for either gene. Further analyses suggest instead that these are sites of increased genomic instability and that they resemble common fragile sites (CFS). Genome-wide analysis revealed properties of CFS-like recurrent deletions that distinguish them from deletions affecting tumor suppressor genes, including their isolation at specific loci away from other genomic deletion sites, a considerably smaller deletion size, and dispersal throughout the affected locus rather than assembly at a common site of overlap. Additionally, CFS-like deletions have less impact on gene expression and are enriched in cell lines compared to primary tumors. We show that loci affected by CFS-like deletions are often distinct from known common fragile sites. Indeed, we find that each tumor tissue type has its own spectrum of CFS-like deletions, and that colon cancers have many more CFS-like deletions than other tumor types. We present simple rules that can pinpoint focal deletions that are not CFS-like and more likely to affect functional tumor suppressors.
authors.affiliation: Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, New York, United States of America.
authors.forename: Megha
authors.initials: M
authors.lastname: Rajaram
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.forename: Tim
authors.initials: T
authors.lastname: Wang
authors.forename: Jinyu
authors.initials: J
authors.lastname: Li
authors.forename: Cem
authors.initials: C
authors.lastname: Kuscu
authors.forename: Huan
authors.initials: H
authors.lastname: Qi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kato
authors.forename: Vladimir
authors.initials: V
authors.lastname: Grubor
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Weil
authors.forename: Aslaug
authors.initials: A
authors.lastname: Helland
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Borrenson-Dale
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Cho
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Lois
authors.initials: L
authors.lastname: Myeroff
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: Michael
authors.initials: M
authors.lastname: Zhang
authors.forename: Alex
authors.initials: A
authors.lastname: Krasnitz
authors.forename: Robert
authors.initials: R
authors.lastname: Lucito
authors.forename: David
authors.initials: D
authors.lastname: Mu
authors.forename: R Scott
authors.initials: RS
authors.lastname: Powers
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D043283:Chromosome Fragile Sites / Q000235:genetics; D002874:Chromosome Mapping; D002875:Chromosomes / Q000235:genetics / Q000378:metabolism; D055028:Comparative Genomic Hybridization; D045643:DNA Repair Enzymes / Q000235:genetics; D016678:Genome / Q000235:genetics*; D006801:Humans; D006867:Hydrolases / Q000235:genetics; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000503:physiopathology; D000072260:RNA Splicing Factors / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017384:Sequence Deletion; D014183:Transplantation, Heterologous
chemical_list: C523332:MACROD2 protein, human; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D006867:Hydrolases; D045643:DNA Repair Enzymes